Throughout this disclosure, various publications, patents and published patent specifications are referenced by an identifying citation. The disclosures of these publications, patents and published patent specifications are hereby incorporated by reference in their entirety into the present disclosure, thereby to describe the state of the art to which this invention pertains.
Cardiac arrhythmia, also known as “dysrhythmia,” is a rubric for a group of conditions characterized by abnormal electrical activity in the heart. Examples of arrhythmias include premature ventricular contractions, ventricular tachycardia, ventricular fibrillation and supraventricular tachyarrhythmia such as atrial fibrillation. By example, atrial fibrillation (AF) is a supraventricular tachyarrhythmia characterized by uncoordinated atrial activation with consequent deterioration of atrial mechanical function. Persistent and/or chronic AF is associated with increased risk of thromoembolic events including MI and stroke and heart failure. Theories of the mechanism of AF involve two main processes: enhanced automaticity in one or several rapidly depolarizing foci and reentry involving one or more circuits.
AF is the most common arrhythmia requiring medical care, with a prevalence of almost 1% in the adult U.S. population (projection of 6 million in U.S. in 2006 and 9 million by 2020). Its prevalence increases with age, such that 8% of people >80 years old have AF. As U.S. and European demographics shift toward an older population, AF will become an even more prevalent cardiovascular disease. Recurrent episodes of AF occur in patients on average 50%/year. Accordingly, AF is a major strain on the health care system, with an average cost in the United States of $3600 per case per annum.
AF is associated with symptoms which adversely affect quality of life including, for example, shortness of breath, chest discomfort or pain and exercise intolerance. The longer the patient remains in AF the greater the risk of thrombus formation in the atria and hence risk of thromboembolic stroke, and hence the need for chronic anticoagulant therapy. It is felt that a large percentage of all stroke cases in the U.S. are secondary to persistent or chronic AF. Other serious cardiac events occurring at significantly higher incidence in AF patients include heart failure and myocardial infarction (MI).
Treatment of AF revolves around cardioversion and use of anticoagulents in persistent and chronic cases. Cardioversion of patients with acute symptomatic AF or paroxsysmal AF can be achieved by means of the use of antiarrhythmic drugs (AADs) or electrical cardioversion to restore sinus rhythm (SR). Alternatively, the physician may elect to simply control rate using drugs which slow AV node conduction and hence control ventricular response rate in patients with AF.
A large controversy currently exists as to whether rhythm control is superior to rate control of patients, although most opinion leaders would prefer their patients be in SR and have no need for anticoagulation. Studies evaluating incidence of serious cardiovascular (CV) sequeli or death with either approach are at this time inconclusive. Cardioversion by defibrillation is not a trivial undertaking, requiring patients to be sedated under the case of an anesthesiologist first and is associated with significant incidence of muscle pain and skin burns. Anti-arrhythmic drugs fall into a number of pharmacologic classes based on the mechanism of actions. There are five recognized AAD classes:
Class I: Na-channel blockers
Class II: Beta-blockers
Class III: K-channel blockers
Class IV: Ca-channel blockers
Class V: Miscellaneous (adenosine, digoxin, etc.)
The development of new anti-AF drugs has unfortunately, at this point, not increased the popularity of pharmacological cardioversion due to low efficacy rates, the risks of drug-induced torsades de pointes (TdeP), ventricular tachycardia, or other serious arrhythmias associated with currently available agents. Pharmacological cardioversion is still less effective than electrical cardioversion and, hence, defibrillation remains the mainstay of treatment of refractory acute atrial fibrillation.
Most marketed agents, e.g., propofenone, flecanide and ibutalide, carry risk of inducing TdeP; hence, most of these agents are not recommended for use in patients suffering from any of and having history of any of ischemic heart disease, prior MI, and prolonged QT syndrome. A number of these agents, such as sotalol, flecanide, propafenone and dronadarone, also display negative effects on contractility of the heart, making them contraindicated in heart failure. The most common severe adverse event is a pro-arrhythmic effect, which is usually associated with blockade of the human Ether-à-go-go-related gene (hERG)-encoded potassium channel IKr, resulting in QT-interval prolongation and potentially fatal ventricular arrhythmia TdeP. Notably, Na-channel blockers that lack inhibitory activity on IKr also may be highly pro-arrhythmic (flecanide) in association with their ability to increase action potential duration, leading to Ca overload in a pronounced fashion and inducing re-entry rhythms.
Although anti-arrhythmic agents such as Na-channel blockers (Class I), Ca-channel blockers (Class IV) and beta-blockers (Class II), and digoxin and adenosine (Class V) all have some anti-AF properties, Class III anti-arrhythmic agents, which are all K-channel inhibitors and by recent consensus of medical experts mixed-channel blockers, are preferred for the anti-AF indication due to their perceived safety advantage and potency in atrial arrhythmia. Recurrent acute AF, persistent AF and paroxsysmal AF eventually lead to the development of chronic AF, there is electrical remodeling in atrial tissue, an adaptive response wherein the relative contributions of different atrial expressed ion channels change. This alteration in channel trafficking is manifested by the shortening of action potential (AP) duration, with a relatively greater contribution from the ultra rapid potassium current IKur, the transient outward potassium current Ito, and the muscarinic acetylcholine potassium current IKAch, as well as a decreased influence of the delayed rectifying potassium current, which has two components: rapid [IKr] and slow [IKs]) and the calcium current. Chronic AF is intractable to medical intervention and maintaining SR in these patients is very difficult; leading to the statement that AF begets AF.
Currently available AADs that target potassium channels tend to block the late Phase 3 repolarizing currents, IKr and IKs, which may make them less effective during AF because Phase 3 is shortened by chronic AF, although this hypothesis has not been proven with certainty. Currently available AADs also target the same ion channels in the ventricle, which can prolong the QT interval, resulting in enhanced risk of TdeP. AADs with selectivity for the atrial specific channels (IKur, Ito, IKAch), which are more active after the electrical remodeling of AF, might provide effective rhythm control with minimal ventricular pro-arrhythmic risk, although down regulation of at least one of these atrial selective channels, IKAch, has been reported with persistent/chronic AF.
Sulcardine, 4-methoxy-N-(3,5-bis-(1-pyrrolidinyl)-4-hydroxy benzyl)benzene sulfonamide, and its salts, such as sulcardine sulfate, constitute a group of new chemicals with potent anti-arrhythmic activity. Sulcardine is a multi-ion (fast and slow Na, L-Ca, and KIto) channel blocker and represents what may be the sole example of a substituted sulfonamide class of anti-arrhythmic. Sulcardine salts can be used as an intravenous injectable or as oral doses for the treatment of arrhythmias, including supraventricular tachyarrhythmia, premature ventricular contractions, ventricular tachycardia and ventricular fibrillation.
In addition, the evidence to date suggests that one advantage of sulcardine and salts is that they lack significant pro-arrhythmic activity, as demonstrated in rigorous preclinical safety models, including a post-MI sudden-death conscious canine model and the validated rabbit ventricular wedge model. Additionally, it has been shown that they do not increase defibrillation threshold, nor increase defibrillation failure risk in a post-MI canine model as was seen with flecanide. On the basis of these data, sulcardine and salts, with their very low apparent pro-arrhythmic potential, could potentially be used to treat acute and recurrent atrial fibrillation in the presence of organic heart disease, prolonged QR syndrome, and ventricular arrhythmias, including premature ventricular contractions (PVCs), ventricular tachycardia (VT), and ventricular fibrillation (VF), in either acute- or chronic-administration settings owing to their ability to be formulated into intravenous and oral dosing formulations.